1. Field of the Invention
The present invention relates to a novel heterocyclic compound which has an oxime group, and has an Inhibitory activity on STAT6 activation.
2. Description of Related Art
IgE, which is an immunoglobulin, is believed to be involved in generating the symptoms of allergic diseases such as bronchial asthma, atopic dermatitis or pollenosis and the like.
After being produced in a B-cell due to sensitization by an allergen, an antigen-specific IgE binds to an IgE receptor of a mast cell. It is known that when a human body is re-exposed to the allergen, binding of the allergen and the IgE triggers mast cell degranulation, releasing inflammatory mediators such as histamine, thereby giving rise to an allergic inflammation. (Refer to Non-Patent Reference 1)
Here, IL-4 and IL-13, which are cytokines generated by type II helper T-cells (Th2 cells), are said to play a central role in a series of allergic reactions: activation of B-cell that generate IgE, proliferation of mast cells and acceleration of histamine secretion. (Refer to Non-Patent Reference 1)
STAT6 protein is known as an important transcription factor that transmits signals from cytokines such as IL-4 and IL-13, and there are reports that when a signaling pathway involving STAT6 is blocked, the action by IL-4 and IL-13 become ineffective, and that in a STAT6 knock-out mouse, inflammation of the respiratory tract and increase in hypersensitivity of the respiratory tract due to sensitization by an allergen are not observed at all. (Refer to Non-Patent References 2 to 4)
Accordingly, since a compound that possesses an inhibitory action on STAT6 activation, in addition to being considered to be effective for the prevention or the treatment of allergic diseases, can also be thought to have an effect on the balance and adjustment of the immune system, it can also be considered to be effective for the prevention or the treatment of autoimmune disease, various infectious diseases, obesity, hyperphagia, malignant tumor or acquired immune deficiency syndrome (AIDS) and the like.
Currently, for instance, Patent References 1 to 4 and the like describe the compounds having an inhibitory activity on STAT6 activation. However, the compounds described in Patent References 1 to 4 have chemical structures that are totally different from a 5 membered ring compound having an oxime group, which is a compound according to the present application.
On the other hand, 5 membered ring compounds having an oxime group with a similar structure to the compound according to the present application are described in Patent References 5 to 8, Non-Patent References 5 to 6 and the like.
However, the compounds included in the present application are not described in these references, in addition, no description is given at all on the inhibitory activity on STAT6 activation in any of these references, and uses of the references differ entirely from those of the present application.
[Patent Reference 1] Japanese Patent Laid-open Publication No. H10-175964
[Patent Reference 2] Japanese Patent Laid-open Publication No. H10-175965
[Patent Reference 3] Japanese Patent Laid-open Publication No. H11-106340
[Patent Reference 4] Japanese Patent Laid-open Publication No. H11-116481
[Patent Reference 5] WO 03/11851
[Patent Reference 6] WO 00/50390
[Patent Reference 7] U.S. Pat. No. 4,108,867
[Patent Reference 8] Japanese Patent Laid-open Publication No. 2003-238565
[Non-Patent Reference 1] Medical Term library: Allergy, Yodosha, (1996)
[Non-Patent Reference 2] Izuhara K., J. Biol. Chem. 271, 619 (1996) [Non-Patent Reference 3] Akimoto,T et al., J. Exp. Med., 187, 1537, 1998;
[Non-Patent Reference 4] Kuperman D et al, J. Exp. Med., 187, 939, 1998
[Non-Patent Reference 5] Bulletin de la Societe Chimique de France, 479-484, 1963
[Non-Patent Reference 6] Khimiya Geterosiklicheskikh Soedinenii, 9, 1178-1180, 1986